Chain extenders

ABSTRACT

The present invention relates to chain extenders, processes for their preparation and their use in the preparation of biocompatible biodegradable polyurethanes and polyurethane ureas for biomedical applications such as stents, scaffolds for tissue engineering. 
     The chain extenders comprise a compound of formula (I)

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of application Ser. No.13/164,316, filed on Jun. 20, 2011. Application Ser. No. 13/164,316 is acontinuation application of application Ser. No. 11/992,340, filed onJun. 9, 2008, which is a National Phase filing under 35 U.S.C. §371 ofPCT/AU2006/001380, filed on Sep. 20, 2006, which claims priority toAustralian Patent Application No. 2005905192, filed on Sep. 20, 2005;the entire contents of all are hereby incorporated by reference.

FIELD

The present invention relates to chain extenders, processes for theirpreparation and their use in the preparation of biocompatiblebiodegradable polyurethanes and polyurethane ureas for biomedicalapplications such as stents, orthopaedic fixation scaffolds andscaffolds for tissue engineering.

BACKGROUND

Biodegradable polyurethanes and polyurethane ureas are typicallyformulated using polyester polyols, aliphatic diisocyanates and diol ordiamine chain extenders. The polyester polyol forms the ‘soft’ segmentof the polymer while the diisocyanate and the chain extender form thehard segment. The hard segment forms ordered domains due to hydrogenbonding and imparts high mechanical strength to the material. The softdomains are formed largely by the polyester polyol and provides elasticproperties to the polymer. Polyester polyols such as polycaprolactone,polyglycolide and polylactide are the most widely used polyols inbiodegradable polyurethanes. The biodegradation of these polymers occurlargely due to the hydrolytic degradation of the ester, urethane andurea linkages of the polymer. The soft segment of the polyurethanedegrades significantly faster than the hard segment. This is largely dueto the presence of relatively easily hydrolysable ester linkages and theamorphous nature of the soft segment. The hard segment of biodegradablepolyurethanes is formed from diisocyanates such as hexamethylenediisocyanate (HDI), butane diisocyanate (BDI), lysine diisocyanate ethylester and lysine diisocyanate methyl ester. The chain extenders are lowmolecular weight (typically MW<400) diols or diamines. Examples include1,4-butanediol, ethylene glycol, ethylene diamine and water. The diolsand diisocyanates react to form urethane linkages in the hard segment ofthe polyurethane. The diamine chain extenders and water react to formurea linkages. The urethane or urea linkages in the hard segment alsodegrade by hydrolysis but at a significantly slower rate than esterlinkages.

An important consideration in the design of biodegradable polymers isthe choice of precursors that would lead to polyurethanes with backbonefunctional groups susceptible to one or more degradation pathways in thebody, such as hydrolytic or enzymatic degradation. Such polyurethanesdegrade to low molecular weight products which are either bloresorbed orreleased from the body through one of the waste disposal pathways in thebody. The use of conventional diisocyanates and chain extenders such asethylene glycol or ethylene diamine leads to polyurethane with hardsegments with urethane, urea or a combination of such functional groups.Because of the relatively slow degradation rates of these linkagescompared with ester linkages, the polymer degradation may lead tooligomers containing mainly hard segments. This becomes a major concern,particularly when polyurethanes are formulated with a higher percentageof hard segment (longer hard segment lengths). Accordingly, it isdesirable if the hard segments also break down rapidly to low molecularweight compounds for rapid release from the body. This also broadens theformulation options for the design of biodegradable polyurethanes withdegradation rates tailored to specific applications.

Chain extenders which break down to biocompatible compounds such asamino acids have been used for formulating biodegradable polyurethanes.The chain extenders are diamines based on cyclohexane dimethanol andphenyl alanine and are generally too high in molecular weight (MW 438)to be considered as chain extenders. The high molecular weight combinedwith the bulky benzyl pendant groups leads to polyurethanes withdisrupted hard segments, limiting the range of properties that can beachieved using such chain extenders in polyurethanes.

SUMMARY

The present invention relates to chain extenders with one or morehydrolysable (degradable) functional groups in the backbone.

The chain extenders are based on ester diols of hydroxy acids ordicarboxylic acids which optionally contain a free radicallypolymerisable functional group(s) in the backbone.

According to one aspect of the present invention there is provided achain extender comprising a compound of formula (I):

in which

r, s, t, u and v are independently 0 or 1 provided that at least two ofr, s, t, u and v are 1;

X and X₁ are O, S or NR in which R is H or optionally substituted C₁₋₆alkyl;

R₁, R₂ and R₃ are independently selected from optionally substitutedC₁₋₂₀ alkylene and optionally substituted C₂₋₂₀ alkenylene both of whichmay be optionally interrupted by optionally substituted aryl oroptionally substituted heterocyclyl.

In a preferred embodiment there is provided a chain extender comprisinga compound of formula (I) in which

r, s, t, and u are independently 0 or 1, v is 0, provided that at leasttwo of r, s, t, and u are 1 and that at least one of s or t is 1;

X₁ is O, S or NR in which R is H or optionally substituted C₁₋₆ alkyl;

X is O or S;

R₁, R₂ and R₃ are independently selected from optionally substitutedC₁₋₂₀ alkylene and optionally substituted C₂₋₂₀ alkenylene both of whichmay be optionally interrupted by optionally substituted aryl oroptionally substituted heterocyclyl.

According to another aspect of the present invention, there is provideda chain extender of formula (I) defined above provided that when r and sare 1, t, u and v are 0, X is O and R₂ is (CH₂)₂, then R₁ is not CH₂,CHCH₃ or (CH₂)₃ (GA-EG, LA-EG or EG-4HB).

Examples of compounds covered by formula (I) are shown in the followingtable:

r s t u v Dimer diol 1 1 0 0 0 Trimer diol 1 0 1 1 0 Dimer acid 0 1 1 00 Trimer acid 0 0 1 1 1 Dimer hydroxy 0 0 1 1 0 acid

The present invention also provides use of the compound of formula (I)defined above as a chain extender.

The present invention further provides the compound of formula (I) asdefined above when used as a chain extender.

Some of the compounds of formula (I) are novel per se and form part ofthe invention such as ε-caprolactone and ethylene glycol dimer (CL-EG).

The present invention also provides a process for the preparation of thecompound of formula (I) defined above which comprises the step oftransesterification of a compound of formula (II) or (III):

in which R₂ is as defined above and n is an integer from 1 to 50,with a compound of formula (IV)HOR¹OH  (IV)in which R₁ is as defined above.

It will be appreciated that the compound of formula (I) may be used incombination with a conventional chain extender.

According to another aspect of the present invention there is provided achain extender composition comprising the compound formula (I) definedabove and a conventional chain extender.

The chain extender and chain extender composition are particularlyuseful in preparing biocompatible biodegradable polyurethane orpolyurethane ureas for biomedical applications.

According to a still further aspect of the present invention there isprovided a biocompatible biodegradable polyurethane or polyurethane ureacomprising a segment formed from the chain extender or chain extendercomposition defined above.

In one embodiment the biocompatible biodegradable polyurethane orpolyurethane urea comprises a reaction product of an isocyanate, polyoland the chain extender or chain extender composition defined above.

In another embodiment, the biocompatible biodegradable polyurethane orpolyurethane urea may also be prepared using only an isocyanate and achain extender or chain extender composition defined above. The chainextender in this instance has a dual functionality as both a chainextender and a polyol.

The biocompatible biodegradable polyurethanes or polyurethane ureas areparticularly useful as scaffolds for coronary artery, blood vessels orcardiac tissue, wound repair, plastic or cosmetic surgery, nerveregeneration, spinal disc repair or augmentation, orthopaedic or tissueengineering applications.

Thus, the present invention also provides a biocompatible biodegradablepolymeric scaffold comprising a cross-linked or linear polyurethane orpolyurethane urea as defined above.

In one embodiment, the scaffold is a stent; stent coating; bonesubstitute; bone filler; bone cement; an orthopaedic fixation scaffoldsuch as a screw, pin, plate or spinal cage or a dart arrow, pin oradhesive for soft tissue repair including meniscal and articularcartilage, tendons ligaments and connective tissue; or a filler forvertobroplasty or kyphoplasty.

The present invention further provides a medical device or compositionwhich is wholly or partly composed of the scaffold defined above.

DETAILED DESCRIPTION

Chain Extender

The term “chain extender” refers to a lower molecular weight compoundhaving two or more functional groups that are reactive towardsisocyanate and having a molecular weight of less than 400.

The chain extenders of the present invention have one or morehydrolysable (degradable) functional groups in the backbone. The term“hydrolysable (degradable) functional group” refers to any molecularmoiety which may be part of the chain extender and is preferablybiocompatible and bioresorbable on in vivo degradation of thebiocompatible biodegradable polyurethane or polyurethane urea which isformed from the chain extender.

The chain extenders of the present invention are based on ester diols ofα-hydroxy acids or dicarboxylic acids which optionally contain freeradically polymerisable functional group(s) in the backbone. When thesechain extenders are used either alone or in combination withconventional chain extenders to form polyurethanes or polyurethaneureas, the polyurethanes degrade at faster rates than those based onconventional chain extenders. Furthermore, the polyurethanes orpolyurethane ureas degrade to low molecular weight compounds due to thedegradation of the hard segment which is formed from the chain extendersof the present invention at rates comparable to that of the soft segmentwhich results in minimum levels of oligomeric hard segment species amongthe degradation products. The chain extenders based on ester diols ofdicarboxylic acids provide two hydrolysable (degradable) functionalgroups within the chain extender backbone to facilitate even fasterbreak down of the hard segment structure. The presence of a freeradically polymerisable functional group in the backbone alsofacilitates cross linking of the hard segment. Polyurethanes orpolyurethane ureas based on these chain extenders can be processed andsubsequently cross linked to form network structures with improvedmechanical properties.

Preferred chain extenders of formula (I) have the formula (Ia) and (Ib)shown below.

in which R₁ to R₃ are as defined above, preferably optionallysubstituted C₁₋₆ alkylene or optionally substituted C₂₋₆ alkenylene.

Representative examples of a compound of formula (Ia) are as follows:

Representative examples of a compound of formula (Ib) are as follows:

The terms “C₁₋₂₀ alkylene” and “C₂₋₂₀ alkenylene” are the divalentradical equivalents of the terms “C₁₋₂₀ alkyl” and “C₂₋₂₀ alkenyl”respectively. The two bonds connecting the alkylene or alkenylene to theadjacent groups may come from the same carbon atom or different carbonatoms in the divalent radical.

The term “C₁₋₂₀ alkyl” refers to linear, branched or cyclic hydrocarbongroups having from 1 to 20 carbon atoms, preferably from 1 to 6 carbonatoms. Illustrative of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term “alkenyl” refers to linear or branched hydrocarbon groupshaving at least one carbon-carbon double bond of 2 to 20 carbon atoms,preferably from 2 to 6 carbon atoms. Examples of alkenyl includeethenyi, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.

The term “aryl” refers to a carbocyclic aromatic system containing one,two or three rings wherein such rings may be attached together in apendent manner or may be fused. The term “aryl” embraces aromaticradicals such as phenyl, naphthyl, tetrahydronaphthyl, indane andbiphenyl.

The term “heterocyclyl” refers to saturated or unsaturated, monocyclicor polycyclic hydrocarbon group containing at least one heteroatomselected from nitrogen, sulphur and oxygen

Suitable heterocyclic groups include N-containing heterocyclic groups,such as, unsaturated 3 to 6-membered heteromonocyclic groups containing1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl ortetrazolyl;

saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino orpiperazinyl;

unsaturated condensed heterocyclic groups containing 1 to 5 nitrogenatoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl ortetrazolopyridazinyl;

unsaturated 3 to 6-membered heteromonocyclic group containing an oxygenatom, such as, pyranyl or furyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulphur atoms, such as, thienyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl oroxadiazolyl;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl;

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl orthiadiazolyl;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl; and

unsaturated condensed heterocyclic group containing 1 to 2 sulphur atomsand 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

The term “optionally substituted” refers to a group may or may not befurther substituted with one or more groups selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, halo, halo C₁₋₆alkyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, haloaryl, hydroxy, C₁₋₆ alkoxy,C₂₋₆alkenyloxy, C₁₋₆aryloxy, benzyloxy, halo C₁₋₆alkoxy, haloalkenyloxy,haloaryloxy, nitro, nitroC₁₋₆alkyl, nitroC₂₋₆alkenyl, nitroC₂₋₆alkynyl,nitroaryl, nitroheterocyclyl, amino, C₁₋₆alkylamino, C₁₋₆dialkylamino,C₂₋₆alkenylamino, C₂₋₆alkynylamino, arylamino, diarylamino, benzylamino,dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino,diacylamino, acyloxy, C₁₋₆alkylsulphonyloxy, arylsulphenyloxy,heterocyclyl, heterocyclyloxy, heterocyclylamino, haloheterocyclyl, C₁₋₆alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto,C₁₋₆alkylthio, benzylthio, acylthio, phosphorus-containing groups andthe like. Preferred optional substituents are methyl, ethyl, propyl,butyl, and phenyl.

Process

The chain extenders may be prepared by transesterification of anα-hydroxy acid or dicarboxylic acid polymer of formula (II) with analkane diol of formula (III) which is preferably present in an excessamount. Examples of α-hydroxy acids include glycolic acid, L-Lacticacid, D,L-lactic acid, 3-hydroxy propionic acid, 4-hydroxy, butyricacid, 3-hydroxy butyric acid and 5-hydroxy pentanoic acid. Examples ofdicarboxylic acids include succinic acid, fumaric and maleic acid.Examples of alkane diols include ethylene glycol, propylene glycol,butane diol, pentane diol and hexane diol. The chain extender preparedby this process may then be purified using any suitable known techniquesuch as fractional distillation, solvent fractionation, chromatographicseparation such as preparative gel permeation or high performance liquidchromatography.

Chain Extender Composition

The conventional chain extender is preferably difunctional and may bediols, dithiols, diamines, amino acids or dicarboxylic acids. Examplesinclude diols such as ethylene glycol, diethylene glycol, tetraethyleneglycol, 1,3-propane diol, 1,4-butane diol and 1,6-hexane diol; diaminessuch as butane diamine, ethanolamine, glycine and lysine; and dithiolssuch as alkyldithiols, i.e. ethane or propane dithiol.

Polyurethane or Polyurethane Ureas

The biocompatible biodegradable polyurethanes or polyurethane ureas ofthe present invention are preferably prepared by reacting an isocyanate,polyol and the chain extender or chain extender composition definedabove.

Preferably the polyurethanes or polyurethane ureas are thermoplastic andof the general formula:

in which R_(x) is from the isocyanate, R_(y) is from the chain extenderand R_(z) is from the soft segment polyol. The pronumeral ‘q’ representsthe average number of repeat units in the hard segment. The pronumeral‘r’ represents the average number of repeat units in the soft segment.The pronumeral ‘s’ is proportional to the molecular weight of thepolymer and includes both the hard segments repeat units and the softsegment. ‘q’ is an integer between 1 and 100; ‘r’ is an integer between0 and 100, and ‘s’ is an integer between 1 and 500.

Isocyanates suitable for preparation of the polyurethanes orpolyurethane ureas of the invention are those which are selected fromthe group consisting of optionally substituted aliphatic, aromatic andhindered isocyanates or isothiocyanates. Preferably the isocyanate is adiisocyanate.

Examples include isophorone diisocyanate, cyclohexane diisocyanate andthe following:

The term “polyol” refers to a molecule which has at least two or morefunctional hydroxyl groups that can react with isocyanate groups to formurethane groups. Examples of polyols include but are not limited todiols, triols, and macromers such as macrodiols. Preferably the polyolhas a molecular weight of 200-5000, more preferably 200-2000, and evenmore preferably 200-1000. The polyol may be terminated by, for example,a hydroxyl, thiol or carboxylic acid group.

The structure of the polyol is preferably:

in which h and/or k can equal 0 (as is the case of the dimer, eg, h=0,j=1 and k=1) or are integers as is j and R⁴ and R⁷ are independentlyselected from hydrogen, hydroxyl, alkyl, aminoalkyl, (both primary andsecondary) and carboxy alkyl and R⁶ and R⁵ cannot be hydrogen, but canindependently be a linear or branched alkyl, alkenyl, aminoalkyl, alkoxyor aryl. The molecular weight of the entire structure is preferably 120to 400. Less preferably the molecular weight can be up to 2000 and muchless preferably above 2000. Four examples of suitable soft segments areas follows:

-   -   Poly(ε-caprolactone) diol, MW 400: in which R⁶ is (CH₂—CH₂), R⁵        is (CH₂)₅, R⁴ and R⁷ are both H, and j=1 and (h+k)=2.96    -   (Glycolic acid-ethylene glycol) dimer: in which R⁶ is (CH₂—CH₂),        R⁵ is (CH₂), R⁴ and R⁷ are both H, j=1 and (h+k)=1    -   Poly(ethylene glycol), MW 400: in which h=0, k=0, j=˜13, R⁶ is        (CH₂—CH₂), R⁴ and R⁷ are both H    -   Poly(ethylene glycol) bis(3-aminopropyl) terminated (Aldrich);        in which R is (CH₂—CH₂), R⁴ and R⁷ are both —(CH₂)₂NH₂, j=34 and        (h+k)=0

Either or both R⁶ and R⁷ can contain nonlinear structures, for examplewhere R′=(CH₂CHCH₃) which is lactic acid. However, the R⁶ and R⁷ shouldpreferably not contain groups such as OH and NH₂ which are likely tocause crosslinking. Suitable compounds include but are not limited tothe following polyester polyols:

-   -   PGA—Poly-(glycolic acid) diol, in which R is typically        —(CH₂CH₂)—

-   -   PLA—Poly-(lactic acid)diol, in which R is typically —(CH₂CH₂)—

-   -   PCL—Poly-(ε-caprolactone) diol, in which R is typically        —(CH₂CH₂)—

-   -   PEG—Poly-(ethylene glycol)

Examples of other polyols which may act as soft segments includepoly-(4-hydroxybutyrate) diol (P4HB diol), poly-(3-hydroxybutyrate) diol(P3HB diol), polypropylene glycol and any copolymers thereof includingPLGA diol, P(LA/CL) diol and P(3HB/4HB) diol.

Polymeric Scaffolds

Polyols with hydroxyl functionalities greater than 2 can be used whenpreparing thermoset (cross linked) polymers.

It has been found that the polyurethanes or polyurethane ureas accordingto the invention form porous and non-porous cross-linked or linearpolymers which can be used as tissue engineering scaffolds. It has alsobeen found that certain of the biodegradable polyurethanes orpolyurethane ureas according to the invention exhibit a glass transitionbetween room temperature and 37° C. This property can be used to extrudehard materials on FDM apparatus (going in at 20° C.) which will softenand even become elastomeric in vivo or while groups cells on scaffoldsin a bioreactor at physiological temperatures of 37° C. This is also avery useful property for soft tissue applications.

The polymers in both cross linked and linear form can be used tofabricate various types of scaffolds. For example, the linear polymerscan be fabricated to form fibres using techniques such as reactiveextrusion. The fibres can be woven or knitted to fabricate membranesuseful in applications such as wound repair. Likewise, polymers in bothform can be machined or lathed to form orthopaedic fixation scaffoldssuch as screws, pins, plates and spinal cages. Such devices aretypically prepared by compression moulding the polymers as a solid orporous block and machined to form the appropriate scaffold structure.

The polyurethanes or polyurethane ureas can be sterilized without riskto their physical and chemical characteristics, preferably using gammaradiation to ensure sterility.

The polyurethanes or polyurethane ureas may incorporate biological andinorganic components selected for their ability to aid tissue repair invivo. When cured, the polyurethanes or polyurethane ureas according tothe invention form a biodegradable biocompatible scaffold which may beporous and contain interpenetrating polymer networks so as to enable theinclusion of biological and inorganic components. These biological andinorganic components which are preferably selected from the groupsconsisting of cells, progenitor cells, growth factors, other componentsfor supporting cell growth, drugs, calcium phosphate, hydroxyapatite,hyaluronic acid, nonparticulate tricalcium phosphate and hydroxyapatitetype fillers, radio opaque substances including barium sulfate andbarium carbonate, adhesives including fibrin, collagen andtransglutaminase systems, surfactants including siloxane surfactants,silica particles, powdered silica, hollow fibres which may be used toseed cells in the polyurethanes, and other porogens including forexample, gelatin beads. The biological and inorganic components may bepresent in quantities according to need, especially in the case of theliving additives such as cells and progenitor cells. Amounts of up to aleast 20% w/w may be acceptable.

The scaffolds may preferably incorporate biological and inorganiccomponents which are desirably selected from the group consisting ofcells, progenitor cells, growth factors, other components for supportingcells growth, drugs, calcium phosphate, hydroxyapatite, hyaluronic acid,non particulate tricalcium phosphate and hydroxyapatite type fillers,adhesives including fibrin, collagen and transglutaminase systems,surfactants including siloxane surfactants, silica particles, powderedsilica, hollow fibres which may be used to seed cells in thepolyurethanes or polyurethane ureas, and other porogens including, forexample, gelatin beads. The biological and inorganic components may bepresent in quantities according to need, especially in the case of theliving additives such as cells and progenitor cells. Amounts of up to atleast 20% w/w may be acceptable.

Preferably the cured scaffolds according to this aspect of the inventionhave a compressive strength in the range of 0.05-200 MPa The compressivestrength of the scaffold will vary according to its porosity andaccording to the biological components added. Preferably the scaffoldshave pores in the size range of 100-500 micron, more preferably 150-300micron.

More preferably the porous scaffolds are seeded with living biologicalcomponents or drugs selected so as to aid the tissue repair process inthe patient being treated. The biological components so selected may becells, progenitor cells, growth factors and other components forsupporting cell growth. Suitable cells may include osteoblasts,chondrocytes, fibroblasts or other precursor cells. Suitable drugs areany which assist in the tissue engineering application of interest.

Preferably the scaffold is a biodegradable stent useful in treatment ofcoronary heart disease. In another aspect of the invention, thebiodegradable biocompatible polyurethanes or polyurethane ureas of theinvention are used as stent coatings in the treatment of coronary heartdisease.

There is also provided a use of polyurethanes or polyurethane ureasaccording to the invention in tissue repair or engineering comprisinginserting in a subject in need of such treatment a scaffold comprising across-linked or linear biocompatible biodegradable polyurethane orpolyurethane urea according to the invention.

In the description of the invention, except where the context requiresotherwise due to express language or necessary implication, the word“comprise” or variations such as “comprises” or “comprising” is used inan inclusive sense, i.e. to specify the presence of the stated featuresbut not to preclude the presence or addition of further features invarious embodiments of the invention.

DETAILED DESCRIPTION OF THE DRAWINGS

In the Examples, reference will be made to the accompanying drawings inwhich:

FIG. 1 is an IR Spectrum of GA-1,3-PD, NaCl plate;

FIG. 2 is a ¹HNMR Spectrum of GA-1,3-PD in deuterated DMSO;

FIG. 3 is a ¹³CNMR Spectrum of GA-1,3-PD in deuterated DMSO;

FIG. 4 is a ¹HNMR Spectrum of CL-EG Dimer; and

FIG. 5 is a ¹HNMR Spectrum of CL-BDO Dimer.

EXAMPLES Example I—Preparation of glycolic acid-1,3-propanediol esterdiol (GA-1,3-PD)

Step one—polycondensation or dehydration—56.7 g of glycolic acid washeated at 220° C. to remove water for 5 hours under nitrogen out gassingin a large round-bottomed flask equipped with a magnetic stirrer bead, astill-head sidearm and condenser to collect the water runoff. Theresulting product was polyglycolic acid (PGA), a white solid polymer.Step two—transesterification—To approximately 43 g of white solid PGAwas added 283.6 g of 1,3-propane diol (five to one mole ratio) and thetemperature set at 200° C. for a period of 17 hours and 30 minutes oftransesterification. The glycolic acid ester diol was purified byfractional distillation as outlined below.Step three—Purification by fractional distillation—The dimer-containingliquid was then heated on the Kugelrohr at 50° C. under vacuum(0.01-0.001 torr) to remove unreacted 1,3-propane diol and then thetemperature was increased to 70° C. to distil the dimer. The dimerfraction was collected and then distilled a second time to remove any1,3-propane diol present. The GA-1,3-PD was a white somewhat slurry-likesolid. In total there was 53 g GA-1,3-PD dimer (53% yield).The chemical structure and properties of the ester diol prepared aresummarised in Table 1 below:

TABLE 1 Properties of GA-1,3-PD Abbreviation Chemical StructureCharacterisation GA-1,3-PD

IR, ¹HNMR. ¹³CNMR (Figures 1 to 3)

Example 2—Preparation of Dicarboxylic Ester Diol Chain Extenders

Step one—Condensation—23.6 g of succinic acid (a diacid) was heated with248 g of ethylene glycol (1:10 mole ratio) to 170° C. for 20 hours undernitrogen out gassing in a round-bottomed flask equipped with a magneticstirrer bead, a still-head sidearm and condenser to collect the waterrunoff.Step two—Purification by fractional distillation—The product from stepone was then heated under vacuum (0.01 torr) on the Kugelrohr to removeethylene glycol at 40-50° C. and then increased to 120° C. to distil theEG-Suc-EG trimer which came over as a colourless liquid. Yield was 22.7g, (55.1% yield).

TABLE 2 Properties of dicarboxylic acid ester diols Chemical StructureCharacterisation EG- Suc- EG

IR, ¹HNMR, ¹³CNMR EG- Fum- EG

IR, ¹HNMR, ¹³CNMR

Example 3—Preparation of Polyurethanes Using Chain Extenders of Examples1 and 2

Materials: Poly(ε-caprolactone), (PCL), soft segments (molecular weight426) were dried at 90° C. for 4 hours under vacuum (0.1 torr). HDI(Aldrich) was used as received (colourless). Stannous octoate (Aldrich)was kept moisture free and used as received. The chain extender wassynthesised and distilled then kept sealed, refrigerated and dry untiluse.Method: A mixture of PCL soft segment diol (35.000 g), chain extender(21.311 g) and stannous octoate (0.050 g) were weighed into a 100 mlpredried polypropylene beaker, covered with aluminium foil and heated to70° C. under nitrogen in a laboratory oven. HDI (43.689 g) was weighedin a separate wet-tared predried polypropylene beaker and also heated to70° C. The HDI was then added to the diol/EG/stannous octoate beaker andstirred manually until gelation occurred, at which time the hot viscousmixture was poured onto a Teflon® coated metal tray to cure at 100° C.for a period of about 18 hours. The resulting polymer was clear andcolourless.

TABLE 3 Composition of polyurethanes containing degradable chainextenders Hard Chain Stannous segment extender, HDI PCL-426 OctoatePolyurethane % (g) (g) (g) (g) 1 65 GA-1,3PD, 42.306 35.000 0.050 22.6942 65 EG-Suc-EG, 15.782 15.000 0.043 12.075 3 65 EG-Fum-EG, 15.835 15.0000.043 12.022  4* 65 EG, 9.696 36.732 25.000 0.071  5* 35 EG, 0.64810.121 20.000 0.031 *Comparative polyurethanes formed using thenon-degradable chain extender EGDegradation was Conducted on 1 mm Thick Melt-Pressed Specimens in PBSBuffer pH7.4 for 3 Months at 37° C.

The method for degradation was as per ASTM International standard F1635: Standard Test Method for In vitro Degradation Testing of Poly(L-lactic Acid) Resin and Fabricated Form for Surgical Implants. Inshort, the conditions were: Polymers were meltpressed to 100-200 μmthick and strips were cut 5 mm×45 mm, buffer was 0.1M PBS pH 7.4,temperature was 37° C., solution:specimen ratio was between 100:1 and300:1, 0.1% sodium azide was added as antimicrobial, samples were allplaced in a 50 rpm agitated incubator, 6 specimens per material and onlyone specimen per jar.

TABLE 4 Mass loss and GPC molecular weights before and after degradationof the polyurethanes of Table 3 % Pre Degradation Post Degradation PUMass Loss Mn Mw PD Mn Mw PD % ΔMn 1 0.88 ± 0.1 28,096 46,838 1.67 18,59631,122 1.67 66.2 2 2.82 ± 0.2 15,802 26,973 1.71 13,071 20,673 1.58 82.73 0.51 ± 0.2 34,123 91,025 2.67 19,281 38,163 1.98 56.5 4* 0.42 ± 0.2121,842 443,397 3.64 118,803 531,502 4.47 2.5 5* 1.91 ± 0.2 16,95329,660 1.75 16,920 29,013 1.71 0.2

Example 4—Preparation of CL-EG Dimer

ε-caprolactone (114.14 g) and ethylene glycol (310.35 g) were added to around-bottomed flask and heated to 190° C. overnight with a verticalcondenser to avoid loss of reagents.

The ethylene glycol was removed on the Kugelrohr (0.01-0.001 torr) at40-50° C. and then the CL-EG dimer was distilled at 100° C. CL-EG dimerwas collected and this was redistilled to remove ethylene glycol, giving120 g of CL-EG dimer. The dimer was a colourless low-viscosity liquid.Characterisation was by ¹HNMR (FIG. 4).

Example 5—Preparation of CL-BDO Dimer

ε-caprolactone (79.83 g) and 1,4-butane diol (450.60 g) were added to around-bottomed flask and heated to 180° C. over the weekend (˜66 hours)with a vertical condenser to avoid loss of reagents.

The 1,4-butane diol was removed on the Kugelrohr (0.01-0.001 torr) at80° C. and then the CL-BDO dimer was distilled at 110° C. CL-BDO dimerwas collected and redistilled to remove BDO, giving 63.75 g of CL-BDOdimer. The dimer was a colourless low-viscosity liquid. Characterisationwas by ¹HNMR (FIG. 5).

Example 6—Comparative Hydrolysis at 100° C.

Two polymers from Table 3 can be compared for hydrolytic degradation at100° C. and measured by change in concentration of amine in solution(due to urethane hydrolysis). Approximately 5 g of polymer is weighedout and placed in a round-bottomed flask. Distilled water is then addedto the flask containing the sample such that the sample to water ratiois approximately 1:50 (to obtain concentrated degradation products). Theround-bottomed flask is then placed in an oil bath set to 130° C. andrefluxed for 24 hours with a vertical condenser. The degradationproducts are collected and subjected to the Ninhydrin Assay. NinhydrinAssay: Ninhydrin Reagent Solution is obtained from Sigma, product codenumber N 7285. The protocol on the product information sheet is followedwith regard to the assay as well as the preparation of the standardcurve.

Example 7—Preparation of Cross Linked Polymers Incorporating DegradableChain Extenders

A prepolymer of pentaerythritol (PE) with ELDI (2.0 g) is weighed into aGlass vial. Degassed and dried dimer from Table 3 0.461 g (MW 120) isadded to the prepolymer. The mixture is manually stirred using a spatulafor 3 minutes with stannous 2-ethyl hexanoate catalyst (0.002 g, 0.1%based on based on total weight of prepolymer) and is degassed under avacuum for 5 min. The viscous mixture is taken into a 2.5 ml syringe anddispensed 0.33 g into each cylindrical cavity (6 mm D×12 mm L) in amulti-cavity Teflon mould and cured overnight at 38° C. to givecylindrical polymer test specimens. A second polymer is prepared byincorporating 5 wt-% of β-tricalcium phosphate (TCP, 5 micron particlesize). TCP is added to the reactant mixture and stirred using a highspeed mechanical stirrer for uniform distribution.

The cured polymer samples is tested using Instron (Model 5568) forcompressive strength and modulus according to ASTM method F451-756.

Example 8

Materials: Poly(ethylene glycol (PEG) (molecular weight 1000) is driedat 90° C. for 4 hours under vacuum (0.1 torr). HDI (Aldrich) is used asreceived. Stannous octoate (Aldrich) is kept moisture free and used asreceived. The chain extender is synthesised using the proceduredescribed in Example 1. The distilled product is kept sealed underrefrigerated and dry conditions until use.

Method: The polymer is prepared using the method described in Example 3.A mixture of polyethylene glycol (10.000 g), chain extender (1.713 g),EG (1.330 g) and stannous octoate (0.010 g) are weighed into a 100 mlpredried polypropylene beaker, covered with aluminium foil and heated to70° C. under nitrogen in a laboratory oven. HDI (7.862 g) is weighed ina separate wet-tared predried polypropylene beaker and heated to 70° C.HDI is then added to the polyol/chain extender mixture in a beaker andstirred manually for 3 min. The viscous mixture is then poured onto aTeflon® coated metal tray and cured at 100° C. for a period of about 18hours in a nitrogen circulating oven.

It will be apparent to the person skilled in the art that while theinvention has been described in some detail for the purposes of clarityand understanding, various modifications and alterations to theembodiments and methods described herein may be made without departingfrom the scope of the inventive concept disclosed in this specification.

The invention claimed is:
 1. A biocompatible biodegradable polyurethaneor polyurethane urea comprising a segment formed from a chain extender,wherein the chain extender is a compound of formula (2):

wherein R₁ and R₃ are independently selected from C₁₋₂₀ alkylene andC₂₋₂₀ alkenylene, at least one of which is substituted by one or moregroups selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, halo, halo C₁₋₆ alkyl, halo C₂₋₆ alkenyl, halo C₂₋₆alkynyl, haloaryl, hydroxy, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ aryloxy,benzyloxy, halo C₁₋₆ alkoxy, haloalkenyloxy, haloaryloxy, nitro,nitroC₁₋₆ alkyl, nitroC₂₋₆ alkenyl, nitroC₂₋₆ alkynyl, nitroaryl,nitroheterocyclyl, amino, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₂₋₆alkenylamino, C₂₋₆ alkynylamino, arylamino, diarylamino, benzylamino,dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino,diacylamino, acyloxy, C₁₋₆ alkylsulphonyloxy, arylsulphenyloxy,heterocyclyl, heterocyclyloxy, heterocyclylamino, haloheterocyclyl, C₁₋₆alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, C₁₋₆alkylthio, benzylthio, acylthio and phosphorus-containing groups.
 2. Abiocompatible biodegradable polyurethane or polyurethane urea accordingto claim 1 wherein the aryl group is selected from the group consistingof phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
 3. Abiocompatible biodegradable polyurethane or polyurethane urea accordingto claim 1 wherein the heterocyclyl group is selected from the groupconsisting of unsaturated 3 to 6-membered heteromonocyclic groupscontaining 1 to 4 nitrogen atoms, saturated 3 to 6-memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms, unsaturatedcondensed heterocyclic groups containing 1 to 5 nitrogen atoms,unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygenatom, unsaturated 3 to 6-membered heteromonocyclic group containing 1 to2 sulphur atoms, unsaturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1to 3 nitrogen atoms, saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, andunsaturated condensed heterocyclic group containing 1 to 2 sulphur atomsand 1 to 3 nitrogen atoms.
 4. A biocompatible biodegradable polyurethaneor polyurethane urea according to claim 1 wherein the heterocyclyl groupis selected from the group consisting of pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, pyranyl orfuryl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, morpholinyl,benzoxazolyl, benzoxadiazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,benzothiazolyl and benzothiadiazolyl.
 5. A biocompatible biodegradablepolyurethane or polyurethane urea according to claim 1 wherein at leastone of the substituents of the C₁₋₂₀ alkylene or C₂₋₂₀ alkenylene groupsof R₁ or R₃ comprises a bioactive moiety.
 6. A biocompatiblebiodegradable polyurethane or polyurethane urea according to claim 1comprising the chain extender of formula (2) and another chain extender.7. A biocompatible biodegradable polyurethane or polyurethane ureaaccording to claim 6, in which the other chain extender is a diol,dithiol, diamine, amino acid or dicarboxylic acid.
 8. A biocompatiblebiodegradable polyurethane or polyurethane urea according to claim 1which comprises a reaction product of an isocyanate, polyol and a chainextender.
 9. A biocompatible polyurethane or polyurethane urea accordingto claim 8 in which the polyurethane or polyurethane urea isthermoplastic and of the general formula:

in which R_(x) is from the isocyanate, R_(y) is from the chain extenderand R_(z) is from the soft segment polyol; ‘q’ is the average number ofrepeat units in the hard segment; ‘r’ is the average number of repeatunits in the soft segment; and ‘s’ is proportional to the molecularweight of the polymer and includes both the hard segments repeat unitsand the soft segment; and in which ‘q’ is an integer between 1 and 100,‘r’ is an integer between 0 and 100, and ‘s’ is an integer between 1 and500.
 10. A biocompatible polyurethane or polyurethane urea according toclaim 8 in which the isocyanate is a diisocyanate.
 11. A biocompatiblepolyurethane or polyurethane urea according to claim 8, in which thepolyol is a diol, triol, tetrol, hexol or macrodiol.
 12. A biocompatiblepolyurethane or polyurethane urea according to claim 8, in which thepolyol is terminated by a hydroxyl, thiol or carboxylic acid group. 13.A biocompatible polyurethane or polyurethane urea according to claim 8,wherein the polyol is of general formula:

wherein h and/or k are independently 0 or an integer, j is an integer, Zis a linear or branched alkyl, alkenyl or aryl wherein each occurrenceof Z independently within the segment j may be the same or different andR is a linear or branched alkyl, alkenyl, aminoalkenyl, alkoxy or arylfunction wherein each occurrence of R independently within the segmentsh or k may be the same or different, and wherein one or both of R and Zoptionally comprises a bioactive moiety.
 14. A biocompatiblepolyurethane or polyurethane urea according to claim 13, in which thepolyol is selected from the group consisting of poly(ε-caprolactone)diol, MW 400: in which Z is (CH₂—CH₂), R is (CH₂)₅ and j=1 and(h+k)=2.96; (glycolic acid-ethylene glycol) dimer: in which Z is(CH₂—CH₂), R is (CH₂), j=1 and (h+k)=1; and poly(ethylene glycol), MW400: in which h=0, k=0, j=˜13 and R⁶ is (CH₂—CH₂).
 15. A biocompatiblepolyurethane or polyurethane urea according to claim 8, in which thepolyol has a molecular weight of 200-5000, 200-2000 or 200-1000.